Diagnosis of monoclonal gammopathy of renal significance

Monoclonal gammopathy of renal significance (MGRS) regroups all renal disorders caused by a monoclonal immunoglobulin (MIg) secreted by a nonmalignant B-cell clone. By definition, patients with MGRS do not meet the criteria for overt multiple myeloma/B-cell proliferation, and the hematologic disorder is generally consistent with monoclonal gammopathy of undetermined significance (MGUS). However, MGRS is associated with high morbidity due to the severity of renal and sometimes systemic lesions induced by the MIg. Early recognition is crucial, as suppression of MIg secretion by chemotherapy often improves outcomes. The spectrum of renal diseases in MGRS is wide, including old entities such as AL amyloidosis and newly described lesions, particularly proliferative glomerulonephritis with monoclonal Ig deposits and C3 glomerulopathy with monoclonal gammopathy. Kidney biopsy is indicated in most cases to determine the exact lesion associated with MGRS and evaluate its severity. Diagnosis requires integration of morphologic alterations by light microscopy, immunofluorescence (IF), electron microscopy, and in some cases by IF staining for Ig isotypes, immunoelectron microscopy, and proteomic analysis. Complete hematologic workup with serum and urine protein electrophoresis, immunofixation, and serum-free light-chain assay is required. This review addresses the pathologic and clinical features of MGRS lesions, indications of renal biopsy, and a proposed algorithm for the hematologic workup. Monoclonal gammopathy of renal significance (MGRS) regroups all renal disorders caused by a monoclonal immunoglobulin (MIg) secreted by a nonmalignant B-cell clone. By definition, patients with MGRS do not meet the criteria for overt multiple myeloma/B-cell proliferation, and the hematologic disorder is generally consistent with monoclonal gammopathy of undetermined significance (MGUS). However, MGRS is associated with high morbidity due to the severity of renal and sometimes systemic lesions induced by the MIg. Early recognition is crucial, as suppression of MIg secretion by chemotherapy often improves outcomes. The spectrum of renal diseases in MGRS is wide, including old entities such as AL amyloidosis and newly described lesions, particularly proliferative glomerulonephritis with monoclonal Ig deposits and C3 glomerulopathy with monoclonal gammopathy. Kidney biopsy is indicated in most cases to determine the exact lesion associated with MGRS and evaluate its severity. Diagnosis requires integration of morphologic alterations by light microscopy, immunofluorescence (IF), electron microscopy, and in some cases by IF staining for Ig isotypes, immunoelectron microscopy, and proteomic analysis. Complete hematologic workup with serum and urine protein electrophoresis, immunofixation, and serum-free light-chain assay is required. This review addresses the pathologic and clinical features of MGRS lesions, indications of renal biopsy, and a proposed algorithm for the hematologic workup. Kidney disease is a frequent complication of monoclonal gammopathies that manifests with a wide range of renal lesions. These patterns are mostly determined by the physicochemical characteristics of the pathogenic monoclonal immunoglobulin (MIg).1.Solomon A. Weiss D.T. Kattine A.A. Nephrotoxic potential of Bence Jones proteins.N Engl J Med. 1991; 324: 1845-1851Crossref PubMed Scopus (256) Google Scholar The renal disease may complicate a previously diagnosed clonal B-cell disorder or be the initial manifestation of the hematological disease. Two main categories of renal disorders associated with monoclonal gammopathies should be distinguished, depending on the burden of the underlying plasma cell or B-cell clone. The first group of renal disorders requires the secretion of large amounts of all or part of the MIg and is only observed in the setting of a high tumor mass B-cell proliferation. This is typically illustrated by the massive precipitation of light chain (LC) in the lumen of distal tubules, which characterizes light-chain cast nephropathy, the most common cause of acute kidney injury in multiple myeloma (MM). Light-chain cast nephropathy is considered as a MM defining event because it always forms as the result of high monoclonal LC production, indicating a high tumor burden, a situation that requires urgent introduction of chemotherapy.2.Alexanian R. Barlogie B. Dixon D. Renal failure in multiple myeloma. Pathogenesis and prognostic implications.Arch Intern Med. 1990; 150: 1693-1695Crossref PubMed Scopus (253) Google Scholar,3.Drayson M. Begum G. Basu S. et al.Effects of paraprotein heavy and light chain types and free light chain load on survival in myeloma: an analysis of patients receiving conventional-dose chemotherapy in Medical Research Council UK multiple myeloma trials.Blood. 2006; 108: 2013-2019Crossref PubMed Scopus (74) Google Scholar Although rare, another example is glomerular intracapillary deposition of MIgM to form thrombi in high tumor mass Waldenström’s macroglobulinemia.4.Morel-Maroger L. Basch A. Danon F. et al.Pathology of the kidney in Waldenstrom's macroglobulinemia. Study of sixteen cases.N Engl J Med. 1970; 283: 123-129Crossref PubMed Scopus (117) Google Scholar The other group is renal diseases associated with low-grade lymphoproliferative disorders. Although they may occur during symptomatic B-cell proliferations, these other MIg-related renal lesions are mainly encountered in patients with a small B-cell clone and low malignant potential.5.Merlini G. Stone M.J. Dangerous small B-cell clones.Blood. 2006; 108: 2520-2530Crossref PubMed Scopus (334) Google Scholar Only 8% of patients with immunoglobulin light-chain (AL) amyloidosis6.Kourelis T.V. Kumar S.K. Gertz M.A. et al.Coexistent multiple myeloma or increased bone marrow plasma cells define equally high-risk populations in patients with immunoglobulin light chain amyloidosis.J Clin Oncol. 2013; 31: 4319-4324Crossref PubMed Scopus (153) Google Scholar and 20% of patients with Randall-type monoclonal Ig deposition disease (MIDD)7.Nasr S.H. Valeri A.M. Cornell L.D. et al.Renal monoclonal immunoglobulin deposition disease: a report of 64 patients from a single institution.Clin J Am Soc Nephrol. 2012; 7: 231-239Crossref PubMed Scopus (198) Google Scholar have evidence of a symptomatic MM at diagnosis. This clone can be expressed as any indolent B-cell lymphoid disorder, including the so-called ‘smoldering’ asymptomatic MM and low-grade lymphoplasmacytic lymphoma with Waldenström’s macroglobulinemia, or a monoclonal gammopathy of undetermined significance (MGUS). In this setting, structural peculiarities of the MIg, particularly the variable domain, and not the rate of production, are the main determinants of renal lesions. The nonmalignant nature of these clones has been a source of confusion for clinicians when it comes to treatment. Because many of these clones are best classified as MGUS, defined as a plasma cell proliferative disorder that manifests <3g/dl of monoclonal protein and <10% bone marrow plasma cells, or smoldering MM, defined by >3g/dl of monoclonal protein and/or >10% bone marrow plasma cells but without any end organ damage, chemotherapy is not indicated in patients with MGUS, smoldering MM, or low-grade lymphomas.8.Kyle R.A. Durie B.G. Rajkumar S.V. et al.Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management.Leukemia. 2010; 24: 1121-1127Crossref PubMed Scopus (616) Google Scholar According to the current treatment guidelines, these patients require only clinical and biological surveillance as they may remain asymptomatic over a prolonged period of time, and early therapy has not been shown to be beneficial in the majority of patients. Chemotherapy is only introduced when symptoms related to the underlying lymphocytic or plasmacytic proliferative process develop or are impending. Symptomatic MM is defined by evidence of end organ damage, characterized by CRAB (hyperCalcemia, Renal impairment, Anemia, Bone disease). On the basis of the current guidelines, cytotoxic therapy is often withheld in patients with renal diseases associated with MIg who do not meet the criteria for MM or symptomatic lymphoma.9.Pozzi C. D'Amico M. Fogazzi G.B. et al.Light chain deposition disease with renal involvement: clinical characteristics and prognostic factors.Am J Kidney Dis. 2003; 42: 1154-1163Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar Such an approach is not appropriate for these patients, as despite the absence of high tumor burden, they display high morbidity and even increased mortality. In an effort to address this need, the International Kidney and Monoclonal Gammopathy Research Group (IKMG) had their inaugural meeting in Bath, UK, in 2009. Members of the IKMG come from the disciplines of nephrology, hematology, and nephropathology and from countries around the globe including Austria, Australia, Canada, France, Italy, New Zealand, Spain, United Kingdom, and United States. Through a series of subsequent meetings, the term monoclonal gammopathy of renal significance (MGRS) was refined and introduced in 2012 to distinguish these monoclonal gammopathies from MGUS.10.Leung N. Bridoux F. Hutchison C.A. et al.Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant.Blood. 2012; 120: 4292-4295Crossref PubMed Scopus (378) Google Scholar The main goal was to clearly delineate the benign hematological disorder MGUS, which cannot be associated with any end organ damage, from MGRS that is associated with severe consequences related to MIg deposition in the kidneys (and sometimes in other organs) that considerably increase morbidity and may even impair patient survival. It is important to recognize that like MGUS, the diagnosis of MGRS does not exclude the possibility of future hematologic disease progression. With its clear distinction from the ‘benign’ term of MGUS, treatment strategies for MGRS-related kidney conditions can be formulated without conflict with the current MM treatment guidelines. It should be noted that cytotoxic therapy including stem cell transplantation has been used in AL amyloidosis in which the majority of patients do not meet the criteria for symptomatic MM.11.Jaccard A. Moreau P. Leblond V. et al.High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis.N Engl J Med. 2007; 357: 1083-1093Crossref PubMed Scopus (432) Google Scholar Hence, this is one of the first examples of successful treatment of a MGRS-related kidney disease. The treatment strategy of MGRS is based on chemotherapy that should be adapted to the nature of the underlying clone, either lymphocytic or plasmacytic, to renal function and to the presence or not of extrarenal involvement.12.Fermand J.P. Bridoux F. Kyle R.A. et al.How I treat monoclonal gammopathy of renal significance (MGRS).Blood. 2013; 122: 3583-3590Crossref PubMed Scopus (209) Google Scholar Rapid suppression of the secretion of nephrotoxic MIg has been shown to favorably impact renal and patient survival in most diseases associated with MGRS, including AL amyloidosis, light-chain deposition disease (LCDD), immunotactoid glomerulopathy, and proliferative glomerulonephritis with monoclonal Ig deposits (PGNMID).13.Leung N. Dispenzieri A. Fervenza F.C. et al.Renal response after high-dose melphalan and stem cell transplantation is a favorable marker in patients with primary systemic amyloidosis.Am J Kidney Dis. 2005; 46: 270-277Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 14.Lorenz E.C. Gertz M.A. Fervenza F.C. et al.Long-term outcome of autologous stem cell transplantation in light chain deposition disease.Nephrol Dial Transplant. 2008; 23: 2052-2057Crossref PubMed Scopus (88) Google Scholar, 15.Bridoux F. Hugue V. Coldefy O. et al.Fibrillary glomerulonephritis and immunotactoid (microtubular) glomerulopathy are associated with distinct immunologic features.Kidney Int. 2002; 62: 1764-1775Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 16.Guiard E. Karras A. Plaisier E. et al.Patterns of noncryoglobulinemic glomerulonephritis with monoclonal Ig deposits: correlation with IgG subclass and response to rituximab.Clin J Am Soc Nephrol. 2011; 6: 1609-1616Crossref PubMed Scopus (98) Google Scholar In AL amyloidosis, renal response is closely associated with the magnitude of hematological response, as renal response rate is significantly higher in patients who have achieved a serum-free light-chain (FLC) response of more than 90%.17.Pinney J.H. Lachmann H.J. Bansi L. et al.Outcome in renal Al amyloidosis after chemotherapy.J Clin Oncol. 2011; 29: 674-681Crossref PubMed Scopus (118) Google Scholar Finally, in the absence of an efficient suppression of the nephrotoxic MIg, MGRS-related renal lesions recur in the allograft in most patients, usually within the first year after renal transplantation.18.Czarnecki P.G. Lager D.J. Leung N. et al.Long-term outcome of kidney transplantation in patients with fibrillary glomerulonephritis or monoclonal gammopathy with fibrillary deposits.Kidney Int. 2009; 75: 420-427Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 19.Leung N. Lager D.J. Gertz M.A. et al.Long-term outcome of renal transplantation in light-chain deposition disease.Am J Kidney Dis. 2004; 43: 147-153Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 20.Nasr S.H. Sethi S. Cornell L.D. et al.Proliferative glomerulonephritis with monoclonal IgG deposits recurs in the allograft.Clin J Am Soc Nephrol. 2011; 6: 122-132Crossref PubMed Scopus (98) Google Scholar, 21.Pinney J.H. Lachmann H.J. Sattianayagam P.T. et al.Renal transplantation in systemic amyloidosis-importance of amyloid fibril type and precursor protein abundance.Am J Transplant. 2013; 13: 433-441Crossref PubMed Scopus (64) Google Scholar, 22.Zand L. Lorenz E.C. Cosio F.G. et al.Clinical Findings, Pathology, and Outcomes of C3GN after Kidney Transplantation.J Am Soc Nephrol. 2013; PubMed Google Scholar In addition to AL amyloidosis, the spectrum of MGRS includes various other renal lesions. Most are due to deposition of a MIg fragment with distinct localization and pattern of ultrastructural organization, usually resulting in glomerular disorders but more rarely in tubular disorders such as the Fanconi syndrome (FS). Glomerulopathies are featured either by organized deposits, fibrillar (AL and Ig heavy chains (AH) amyloidosis) or microtubular (type I cryoglobulinemic glomerulonephritis, immunotactoid glomerulopathy), or by non-organized deposits (MIDD and PGNMID). Importantly, our understanding of the spectrum of MGRS is evolving, and, in addition to kidney deposition of a MIg, other mechanisms may be implicated, involving the secretion of various biological factors and/or autoantibody activity of the MIg. Examples include secretion of vascular endothelial growth factor in the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) that may trigger development of renal endothelial cell injury and thrombotic microangiopathy-like lesions,23.Sanada S. Ookawara S. Karube H. et al.Marked recovery of severe renal lesions in POEMS syndrome with high-dose melphalan therapy supported by autologous blood stem cell transplantation.Am J Kidney Dis. 2006; 47: 672-679Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar membranoproliferative glomerulonephritis induced by dimeric monoclonal lambda LC acting as a ‘mini-autoantibody’ against complement factor H,24.Meri S. Koistinen V. Miettinen A. et al.Activation of the alternative pathway of complement by monoclonal lambda light chains in membranoproliferative glomerulonephritis.J Exp Med. 1992; 175: 939-950Crossref PubMed Scopus (179) Google Scholar,25.Jokiranta T.S. Solomon A. Pangburn M.K. et al.Nephritogenic lambda light chain dimer: a unique human miniautoantibody against complement factor H.J Immunol. 1999; 163: 4590-4596PubMed Google Scholar or membranous nephropathy caused by a monoclonal IgG3 kappa targeting the phospholipase A2 receptor.26.Debiec H. Hanoy M. Francois A. et al.Recurrent membranous nephropathy in an allograft caused by IgG3kappa targeting the PLA2 receptor.J Am Soc Nephrol. 2012; 23: 1949-1954Crossref PubMed Scopus (81) Google Scholar Early recognition and prompt characterization of the type of MGRS is crucial, as it determines the therapeutic strategy and strongly impacts renal prognosis.12.Fermand J.P. Bridoux F. Kyle R.A. et al.How I treat monoclonal gammopathy of renal significance (MGRS).Blood. 2013; 122: 3583-3590Crossref PubMed Scopus (209) Google Scholar The purpose of this article is to provide keys for the diagnostic approach to recognize MGRS. In a patient in whom MGRS is suspected, usually based on the coexistence of monoclonal gammopathy and renal symptoms, it is essential to quickly and accurately assess the characteristics of the monoclonal gammopathy, the underlying B-cell clone, the type of nephropathy, and its impact on renal function. Baseline glomerular filtration rate is a major determinant of renal outcome in most types of MGRS, as shown in AL amyloidosis,17.Pinney J.H. Lachmann H.J. Bansi L. et al.Outcome in renal Al amyloidosis after chemotherapy.J Clin Oncol. 2011; 29: 674-681Crossref PubMed Scopus (118) Google Scholar MIDD,7.Nasr S.H. Valeri A.M. Cornell L.D. et al.Renal monoclonal immunoglobulin deposition disease: a report of 64 patients from a single institution.Clin J Am Soc Nephrol. 2012; 7: 231-239Crossref PubMed Scopus (198) Google Scholar and PGNMID.27.Nasr S.H. Satoskar A. Markowitz G.S. et al.Proliferative glomerulonephritis with monoclonal IgG deposits.J Am Soc Nephrol. 2009; 20: 2055-2064Crossref PubMed Scopus (281) Google Scholar In addition, it is mandatory to carefully search for extrarenal manifestations, which may influence prognosis and influence therapeutic decisions. Rapid diagnostic assessment is particularly critical in patients with AL amyloidosis, in whom concomitant heart, liver, or peripheral nerve involvement is frequent, results in decreased survival, and affects therapeutic strategy. Median survival is approximately 6 months in AL patients with significant heart involvement.28.Kyle R.A. Gertz M.A. Greipp P.R. et al.A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine.N Engl J Med. 1997; 336: 1202-1207Crossref PubMed Scopus (627) Google Scholar Efficient chemotherapy based on novel agents such as the cyclophosphamide–bortezomib–dexamethasone regimen is currently recommended in the presence of amyloid cardiomyopathy to achieve rapid and deep hematological response, a key factor for patient survival.29.Palladini G. Dispenzieri A. Gertz M.A. et al.New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes.J Clin Oncol. 2012; 30: 4541-4549Crossref PubMed Scopus (100) Google Scholar,30.Venner C.P. Lane T. Foard D. et al.Cyclophosphamide, bortezomib, and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival.Blood. 2012; 119: 4387-4390Crossref PubMed Scopus (220) Google Scholar Severe extrarenal manifestations are also not uncommon in MIDD and type I cryoglobulinemia, and osteomalacia frequently reveals FS. In patients with symptoms suggestive of systemic AL amyloidosis, minimally invasive biopsies of abdominal fat and minor salivary glands may be performed initially.31.Picken M.M. Amyloidosis-where are we now and where are we heading?.Arch Pathol Lab Med. 2010; 134: 545-551PubMed Google Scholar,32.Merlini G. Wechalekar A.D. Palladini G. Systemic light chain amyloidosis: an update for treating physicians.Blood. 2013; 121: 5124-5130Crossref PubMed Scopus (189) Google Scholar However, in most situations, a kidney biopsy with detailed immunofluorescence (IF) and electron microscopic (EM) studies to identify deposit composition and pattern of organization is needed. Because of the frequency of monoclonal gammopathies in patients aged over 50 years, it is important that the correct correlation of the renal lesions with monoclonal gammopathy is performed, as the presence of a monoclonal protein by itself is not equal to the causative agent. This is illustrated by the fact that up to 10% of patients with hereditary amyloidosis were initially misdiagnosed as AL amyloidosis because of the presence of a serum MIg33.Lachmann H.J. Booth D.R. Booth S.E. et al.Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.N Engl J Med. 2002; 346: 1786-1791Crossref PubMed Scopus (539) Google Scholar and that 10% of patients with amyloidosis derived from leukocyte cell-derived chemotaxin 2, which mainly affects the kidneys, have a serum MIg.34.Said S.M. Sethi S. Valeri A.M. et al.Characterization and outcomes of renal leukocyte chemotactic factor 2-associated amyloidosis.Kidney Int. 2014; 86: 370-377Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Moreover, misdiagnosis of the amyloid subtype may occur, because of nonspecific trapping of the MIg in the amyloid deposits.35.Said S.M. Sethi S. Valeri A.M. et al.Renal amyloidosis: origin and clinicopathologic correlations of 474 recent cases.Clin J Am Soc Nephrol. 2013; 8: 1515-1523Crossref PubMed Scopus (168) Google Scholar In addition, renal biopsy is indicated to assess the MGRS type and evaluate severity of renal disease. This remains important even in patients with advanced chronic kidney disease in whom kidney transplantation is planned, as the disease generally recurs rapidly in the allograft in the absence of control of the underlying clone.18.Czarnecki P.G. Lager D.J. Leung N. et al.Long-term outcome of kidney transplantation in patients with fibrillary glomerulonephritis or monoclonal gammopathy with fibrillary deposits.Kidney Int. 2009; 75: 420-427Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 19.Leung N. Lager D.J. Gertz M.A. et al.Long-term outcome of renal transplantation in light-chain deposition disease.Am J Kidney Dis. 2004; 43: 147-153Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 20.Nasr S.H. Sethi S. Cornell L.D. et al.Proliferative glomerulonephritis with monoclonal IgG deposits recurs in the allograft.Clin J Am Soc Nephrol. 2011; 6: 122-132Crossref PubMed Scopus (98) Google Scholar, 21.Pinney J.H. Lachmann H.J. Sattianayagam P.T. et al.Renal transplantation in systemic amyloidosis-importance of amyloid fibril type and precursor protein abundance.Am J Transplant. 2013; 13: 433-441Crossref PubMed Scopus (64) Google Scholar, 22.Zand L. Lorenz E.C. Cosio F.G. et al.Clinical Findings, Pathology, and Outcomes of C3GN after Kidney Transplantation.J Am Soc Nephrol. 2013; PubMed Google Scholar Kidney biopsy is a safe procedure in patients with MGRS, as shown in a recent study of 148 patients with monoclonal gammopathies in whom the rate of hemorrhagic complications was 4.1%, similar to the control population.36.Fish R. Pinney J. Jain P. et al.The incidence of major hemorrhagic complications after renal biopsies in patients with monoclonal gammopathies.Clin J Am Soc Nephrol. 2010; 5: 1977-1980Crossref PubMed Scopus (47) Google Scholar The spectrum of renal manifestations in MGRS is wide and varies according to disease type and molecular characteristics of the pathogenic MIg (Tables 1, 2, 3). Renal failure and proteinuria, with or without hematuria, are the most common presenting symptoms. Electrophoresis (EP) and immunofixation of a 24-h urine specimen should be performed in all cases to distinguish patients with glomerular involvement who display predominant albuminuria (usually accompanied with secretion of the MIg or a fragment of it) from those with tubulointerstitial lesions.37.Leung N. Gertz M. Kyle R.A. et al.Urinary albumin excretion patterns of patients with cast nephropathy and other monoclonal gammopathy-related kidney diseases.Clin J Am Soc Nephrol. 2012; 7: 1964-1968Crossref PubMed Scopus (55) Google Scholar For instance, in patients with FS, proteinuria typically contains a small amount of albumin but predominantly monoclonal LC and low-molecular weight proteins. These findings should prompt search for symptoms of proximal tubule dysfunction, including normoglycemic glycosuria, uricosuria, phosphaturia, and proximal renal tubular acidosis.38.Bridoux F. Sirac C. Hugue V. et al.Fanconi's syndrome induced by a monoclonal Vkappa3 light chain in Waldenstrom's macroglobulinemia.Am J Kidney Dis. 2005; 45: 749-757Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar,39.Messiaen T. Deret S. Mougenot B. et al.Adult Fanconi syndrome secondary to light chain gammopathy. Clinicopathologic heterogeneity and unusual features in 11 patients.Medicine. 2000; 79: 135-154Crossref PubMed Scopus (179) Google Scholar In those patients without urine abnormalities but impaired glomerular filtration rate and evidence of monoclonal gammopathy, a kidney biopsy should be performed in the absence of an obvious cause of renal disease. Indeed, small cohorts of AL amyloidosis and LCDD patients with predominant vascular/tubulointerstitial deposits and 24h urine protein excretion of less than 0.5g/day have been reported.40.Eirin A. Irazabal M.V. Gertz M.A. et al.Clinical features of patients with immunoglobulin light chain amyloidosis (AL) with vascular-limited deposition in the kidney.Nephrol Dia Transplant. 2012; 27: 1097-1101Crossref PubMed Scopus (45) Google Scholar,41.Sicard A. Karras A. Goujon J.M. et al.Light chain deposition disease without glomerular proteinuria: a diagnostic challenge for the nephrologist.Nephrol Dial Transplant. 2014; 29: 1894-1902Crossref PubMed Scopus (22) Google ScholarTable 1Main clinical, pathological, and immunological characteristics of tubular disorders in MGRSTubular disorderRenal symptomsLight microscopic findingsIF findings (Ig type)Ultrastructural findingsExtrarenal involvementHematological diseaseLight chain Fanconi syndromeProximal tubule dysfunctionaMost common symptoms: hypouricemia, hypophosphatemia, normoglycemic glycosuria, generalized aminoaciduria, low-molecular weight proteinuria, and proximal (type 2) renal tubular acidosis.Slowly progressive CKDPTC atrophy and dedifferentiation Intra-cytoplasmic inclusionsPTC LC inclusionsAlmost always kappa: Vκ1, or Vκ3 (rare)Crystals (rhomboid) within PTC lysosomes or free in the cytoplasmBone (osteomalacia)MGRSSymptomatic MM and WM uncommonProximal tubulopathy without crystalsTubular proteinuria± progressive CKDPTC atrophy and dedifferentiationPTC cytoplasmic swellingPTC LC stainingLambda or kappaAmorphous granular accumulations of LCsIncreased lysosomes with a mottled appearanceNoneMGRSMMCrystal-storing histiocytosisProximal tubule dysfunctionCKDHistiocytes with crystalline inclusions (pseudo-pseudo Gaucher cells) in the interstitium and perirenal fatPTC atrophy and dedifferentiationPTC LC inclusionsMostly kappa :Vκ1 or Vκ3Crystals (needle-shaped) within histiocytes and occasionally in PTC and glomerular cellsBone marrow, liver, spleen, LN, lung, skin, corneaMGRSMMLPLAbbreviations: CKD, chronic kidney disease; IF, immunofluorescence; LC, immunoglobulin light chains; LN, lymph nodes; LPL, lymphoplasmacytic lymphoma; MGRS, monoclonal gammopathy of renal significance; MM, multiple myeloma; PTC, proximal tubular cells; WM, Waldenström’s macroglobulinemia.a Most common symptoms: hypouricemia, hypophosphatemia, normoglycemic glycosuria, generalized aminoaciduria, low-molecular weight proteinuria, and proximal (type 2) renal tubular acidosis. Open table in a new tab Table 2Main clinical, pathological, and immunological characteristics of glomerular disorders with organized Ig deposits in MGRSGlomerular diseaseRenal symptomsLight microscopic findingsIF findings (Ig type)Ultrastructural findingsExtra-renal involvementIdentification of an M-proteinHematological and immunological characteristicsAL amyloidosisAH amyloidosisAHL amyloidosisProteinuria, NS CKDHypertension and hematuria uncommonCongo-red-positive mesangial and CW deposits (dichroism + birefringence under polarized light)Vascular and tubulo interstitial involvement commonAL: LC deposits, mostly lambda AH: HC deposits (γ1, or γ4, or α), with first constant domain (CH1) deletionAHL: LC and HC deposits, mostly γ+λ or α+κRandomly arranged unbranched fibrils 7–14nm in diameterFrequent: heart, liver, peripheral nerveSerum EP/immunofixation: 66-80% in AL, 88% in AH/AHL -Urine EP/immunofixation: 67% in AL, 80% in AH/AHL -FLC: 76-88% in AL, 82% in AH/AHLMGRSSymptomatic MM uncommon WMaIn patients with IgM monoclonal gammopathy.ITGN/GOMMIDProteinuria, NSCKD MicrohematuriaHypertensionMesangial GN with membranous featuresMPGNInterstitial tumoral infiltrate common (CLL)Granular/smudgy deposits in mesangium and CW (pred. subepithelial) Monotypic IgG deposits (IgG1>IgG2>IgG3) (κ>λ)C3, C4, C1q depositsParallely arranged microtubules 10–60nm, with hollow coreUncommon (peripheral nerve, skin)Serum EP/immunofixation: 35–67% Urine EP/immunofixation: 21–53% -FLC: 20%CLL (common)B-cell lymphomaMGRSMM uncommonHypocomp. ∼30%Type I cryoglobulinemicGNProteinuria, NSCKDMicrohematuriaHypertension Possible nephritic syndrome, AKI, anuriaMPGNEndocapillary GNGlomerular thrombi commonIntrarenal vasculitis occasionalGranular deposits in mesangium, CW (pred. subendothelial), vascular wallsGlomerular thrombiMonotypic IgG, IgM, or IgA (κ>λ)- C3, C4, C1q depositsMicrotubules 10 to 90 nmExtra +intracellular crystals (crystal-cryoglobulinemia)Frequent:skin, peripheral nerve, jointsSerum